Coatings for medical devices comprising a therapeutic agent and a metallic material

ABSTRACT

The invention relates generally to an implantable medical device for delivering a therapeutic agent to the body tissue of a patient, and a method for making such a medical device. In particular, the invention pertains to an implantable medical device, such as an intravascular stent, having a coating comprising a first coating composition comprising a therapeutic agent and, optionally, a polymer; and a second coating composition comprising a metallic material.

FIELD OF THE INVENTION

The invention relates generally to implantable medical devices fordelivering a therapeutic agent to the body tissue of a patient, andmethods for making such medical devices. In particular, the inventionpertains to implantable medical devices, such as intravascular stents,having a coating comprising a first coating composition comprising atherapeutic agent and a second coating composition comprising a metallicmaterial.

BACKGROUND OF THE INVENTION

Medical devices have been used to deliver therapeutic agents locally tothe body tissue of a patient. For example, intravascular stentscomprising a therapeutic agent have been used to locally delivertherapeutic agents to a blood vessel. Often such therapeutic agents havebeen used to prevent restenosis. Examples of stents comprising atherapeutic agent include stents that comprise a coating containing atherapeutic agent for delivery to a blood vessel. Studies have shownthat stents having a coating with a therapeutic agent are effective intreating or preventing restenosis.

Even though medical devices having a coating with a therapeutic agentare effective in preventing restenosis, many coated medical devices, inaddition to being coated with a therapeutic agent, are also coated witha polymer. The benefits of using a polymer in such coatings includeeasier loading of therapeutic agents onto the surface of a medicaldevice and the ability to control or regulate the rate of release of thetherapeutic agent.

However, the use of polymers in medical device coatings can also havesome disadvantages. For example, depending on the type of polymer usedto coat the medical device, some polymers can cause inflammation of thebody lumen, offsetting the effects of the therapeutic agent.Additionally, some polymers may also cause thrombosis.

Accordingly, there is a need for coatings for a medical device thatprevent or at least reduce the disadvantages associated with polymercoatings, such as inflammation caused by contact with the body lumen.Moreover, there is a need for a coating for medical devices that cancontrol or regulate the release rate of a therapeutic agent without theuse of polymer coatings. There is also a need for methods of making suchmedical devices.

SUMMARY OF THE INVENTION

These and other objectives are accomplished by the present invention.The present invention provides a medical device, such as an implantable,intravascular stent comprising a coating. The coating is designed toeliminate or at least reduce the amount of polymer contact with the bodytissue, such as a body lumen, while still providing a suitable releaserate of the therapeutic agent. The coating comprises a first coatingcomposition comprising a therapeutic agent and a second coatingcomposition comprising a metallic material. Optionally, the firstcoating composition can further comprise a polymer.

The coating can comprise a first coating composition comprising atherapeutic agent, disposed on the surface of a medical device; and asecond coating composition, which comprises a metallic material andwhich is substantially free of any polymer, disposed on at least aportion of the first coating composition. Metallic materials arematerials containing a metal including but not limited to, metals alloysand oxides. As used herein and unless otherwise defined the phrase“substantially free of any polymer” means having less than or equal to50% of polymer by volume of the composition. With such coatings, polymercontact with the body lumen is reduced or eliminated.

For example, the present invention is directed to an implantableintravascular stent comprising: (a) a stent sidewall structure having asurface; and (b) a coating comprising: (i) a first coating compositioncomprising a therapeutic agent disposed upon at least a portion of thesurface of the stent sidewall structure, wherein the first coatingcomposition, when disposed on the portion of the surface of the stentsidewall structure, has an outer surface; and (ii) a second coatingcomposition comprising a metallic material disposed on at least aportion of the first coating composition, wherein the second coatingcomposition is substantially free of any polymer when applied to theportion of the first coating composition; and wherein after the secondcoating composition is applied to the portion of the first coatingcomposition the second coating composition comprises an outer surfaceand a plurality of pores, in which the pores extend from the outersurface of the first coating composition to the outer surface of thesecond coating composition. In certain embodiments of the presentinvention the second coating composition is disposed on less than theentire outer surface of the first coating composition. Additionally, thesecond coating composition can also be further disposed on a portion ofthe surface of the stent sidewall structure.

The stent sidewall structure can be an abluminal surface or an adluminalsurface. In certain embodiments, the coating is disposed on at least aportion of the abluminal surface. In other embodiments, the firstcoating composition is disposed on at least a portion of the adluminalsurface and the second coating composition is disposed on at least aportion of the first coating composition disposed on the adluminalsurface. In still other embodiments, the first coating composition isdisposed on at least a portion of the adluminal surface and theadluminal surface is free of the second coating composition.

Additionally, the stent sidewall structure can comprise a plurality ofstruts wherein the surface of the stent sidewall structure is theabluminal surface or adluminal surface of at least one of the struts.When the stent sidewall structure comprises a plurality of struts, thecoating can be disposed on at least a portion of the abluminal oradluminal surface of at least one of the struts. For example, thepresent invention is directed to an implantable intravascular stentcomprising: (a) a stent sidewall structure comprising a plurality ofstruts each having an abluminal surface and an adluminal surface (b) afirst coating disposed on the abluminal surface of at least one strutcomprising: (i) a first coating composition comprising ananti-restenosis agent disposed upon at least a portion of the abluminalsurface of the strut, wherein the first coating composition, whendisposed on the portion of the surface of the abluminal surface of thestrut, has an outer surface; and (ii) a second coating compositioncomprising a metallic material disposed on at least a portion of thefirst coating composition, wherein the second coating composition issubstantially free of any polymer; and wherein after the second coatingcomposition is applied to the portion of the first coating compositionthe second coating composition comprises an outer surface and aplurality of pores, in which the pores extend from the outer surface ofthe first coating composition to the outer surface of the second coatingcomposition; and (c) a second coating disposed on at least a portion ofthe adluminal surface of the at least one strut comprising the firstcoating composition.

In certain embodiments, the first coating composition is disposed on atleast a portion of the adluminal surface of at least one of the strutsand at least a portion of the adluminal surface of at least one of thestruts is free of the second coating composition. In other embodiments,the first coating composition is disposed on at least a portion of theadluminal surface of at least one of the struts and the second coatingcomposition is disposed on at least a portion of the first coatingcomposition that is disposed on the adluminal surface.

In certain embodiments, the stent sidewall structure can furthercomprise a plurality of openings therein. When the stent sidewallstructure has a plurality of openings, the first and second coatingcompositions can conform to the stent sidewall structure to preserve theopenings in the stent sidewall structure. For example the presentinvention includes an implantable intravascular stent comprising: (a) astent sidewall structure comprising (1) a plurality of struts eachhaving an abluminal surface and an adluminal surface, and (2) openingsin the stent sidewall structure; (b) a first coating disposed on theabluminal surface of at least one strut comprising: (i) a first coatingcomposition comprising an anti-restenosis agent disposed upon at least aportion of the abluminal surface of the strut, wherein the first coatingcomposition, when disposed on the portion of the surface of theabluminal surface of the strut, has an outer surface; and (ii) a secondcoating composition comprising a metallic material disposed on at leasta portion of the first coating composition, wherein the second coatingcomposition is substantially free of any polymer; and wherein after thesecond coating composition is applied to the portion of the firstcoating composition, the second coating composition comprises an outersurface and a plurality of pores, in which the pores extend from theouter surface of the first coating composition to the outer surface ofthe second coating composition; and (c) a second coating disposed on atleast a portion of the adluminal surface of the at least one strutcomprising the first coating composition, wherein the adluminal surfaceof the at least one strut is free of the second coating composition; andwherein the first and second coatings conform to the stent sidewallstructure to preserve the openings therein.

Also the present invention is directed to an implantable intravascularstent comprising: (a) a stent sidewall structure having a surface; and(b) a coating comprising (i) a first coating composition comprising atherapeutic agent disposed upon at least a portion of the surface of thestent sidewall structure wherein the first coating composition has afirst thickness; and (ii) a second coating composition comprising ametallic material disposed upon at least a portion of the surface of thestent sidewall structure, wherein the second coating composition has asecond thickness and is substantially free of any polymer; and whereinthe first thickness of the first coating composition is not greater thanthe second thickness of the second coating composition. The firstcoating composition can also further comprise a polymer.

In certain embodiments, the second thickness of the second coatingcomposition can be greater than the first thickness of the first coatingcomposition. Alternatively, the first thickness of the first coatingcomposition can be equal to the second thickness of the second coatingcomposition. Moreover, the second coating composition can be disposedadjacent to the first coating composition on the surface of the stentsidewall structure.

In any of the embodiments described above, the first thickness of thefirst coating composition can be about 1 micron to about 30 microns andthe second thickness of the second coating composition can be about 0.1microns to about 50 microns.

The therapeutic agent in the first coating composition can comprise anagent that inhibits smooth muscle cell proliferation. The therapeuticagent in the first coating composition can also comprise ananti-thrombogenic agent, anti-angiogenesis agent, anti-proliferativeagent, antibiotic, anti-restenosis agent, growth factor,immunosuppressant or radiochemical. For example the therapeutic agentcan comprise paclitaxel, sirolimus, tacrolimus, pimecrolimus, everolimusor zotarolimus.

Additionally, the first coating composition further comprises at leastone polymer. Suitable polymers include, but are not limited to,styrene-isobutylene copolymers, polylactic acid andpoly(methylmethacrylate-butyl acrylate-methyl methacrylate).

The metallic material of the second coating composition can be selectedfrom the group consisting of stainless steel, nickel, titanium, chromiumand alloys thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be explained with reference to the followingdrawings.

FIG. 1 shows a cross-sectional view of an embodiment of a coatingdisposed on at least a portion of a medical device.

FIG. 2 shows a cross-sectional view of another embodiment of a coatingdisposed on at least a portion of a medical device.

FIG. 3 shows a portion of a medical device that is suitable for use inthe present invention.

FIG. 4 shows a cross-sectional view of a stent.

FIG. 4 a shows a cross-sectional view of a strut of a stent having acoating thereon.

FIG. 4 b shows a cross-sectional view of another embodiment of a strutof a stent having a coating thereon.

FIG. 5 shows a perspective view of an embodiment of a coating disposedon at least a portion of a stent.

FIG. 6 shows a perspective view of another embodiment of a coatingdisposed on at least a portion of a stent.

FIG. 7 shows a perspective view of yet another embodiment of a coatingdisposed on at least a portion of a stent.

FIG. 8 shows a perspective view of yet another embodiment of a coatingdisposed on at least a portion of a stent.

FIG. 9 shows a cross-sectional view of another embodiment of a coatingdisposed on at least a portion of a medical device.

FIG. 10 shows a cross-sectional view of yet another embodiment of acoating disposed on at least a portion of a medical device.

FIG. 11 shows a cross-sectional view of yet another embodiment of acoating disposed on at least a portion of a medical device.

DETAILED DESCRIPTION

The present invention is directed to a medical device comprising acoating comprising a first coating composition containing a therapeuticagent and optionally a polymer. The medical device also includes asecond coating composition containing a metallic material and issubstantially free of any polymer.

In certain embodiments, the coating comprises a first coatingcomposition comprising a therapeutic agent disposed on the surface ofthe medical device and a second coating composition comprising ametallic material disposed on the first coating composition. The secondcoating composition is substantially free of any polymer. Also, afterthe second coating composition is disposed on the first coatingcomposition, wherein the second coating composition comprises aplurality of pores that extend from the outer surface of the firstcomposition to the outer surface of the second coating composition.

FIG. 1 shows a cross-sectional view an embodiment of a coating disposedon at least a portion of a medical device such as a stent. In thisembodiment, medical device 10 has a surface 12 and a coating 20. Coating20 includes a first coating composition 22 comprising a therapeuticagent 30 disposed on at least a portion of the surface 12 of the medicaldevice 10. When disposed on the surface 12, the first coatingcomposition 22 has an outer surface 22 a. The coating also includes asecond coating composition 24 disposed on at least a portion of thefirst coating composition 22. The second coating composition 24comprises a metallic material and is substantially free of any polymer.The second coating composition 24 can be disposed on a portion of or theentire first coating composition 22.

As shown in FIG. 1, the second coating composition 24 after beingapplied to the first coating composition 22 has an outer surface 24 aand also has a plurality of pores 42. At least some of the pores 42extend from the outer surface 22 a of the first coating composition 22to the outer surface 24 a of the second coating composition 24. Thepores 42 can be partially or completely filled with the first coatingcomposition 22. In either case having the pores that extend from theouter surface 22 a of the first coating composition 22 to the outersurface 24 a of the second coating composition 24 allows the therapeuticagent 30 to be released from the first coating composition 22 underlyingthe second coating composition 24. Additionally, having pores 42 thatallow for fluid communication between the outer surfaces 22 a and 24 acan aid in vascularization, provide long term non-inflammation andminimize or eliminate thrombosis. Furthermore, some or all of the pores42 in the second coating composition 24 can be interconnected to otherpores 42 within the second coating composition 24. In some embodiments,the pores 42 may be disposed in a desired pattern.

In addition, the pores 42 in the second coating composition 24 may haveany shape. For example, the pores 42 can be shaped like channels, voidpathways or microscopic conduits, spheres or hemispheres. Additionally,the pores 42 in the second coating composition 24 may have any size orrange of sizes. In some instances, the pores 42 can be micropores ornanopores. Also, in some embodiments, it may be preferable that thewidth or diameter of the pores 42 is between about 1 nm and about 10 μm.

The size of the pores 42 can also be used to control the release rate ofthe therapeutic agent 30. For example, pores 42 having a larger widthwill allow the therapeutic agent 30 to be released more quickly thanpores 42 with a smaller width. Also, the number of pores 42 in thesecond coating composition 24 can be adjusted to better control therelease rate of the therapeutic agent 30. For example, the presence ofmore pores 42 per unit volume or weight of the second coatingcomposition 24 can allow for a higher release rate of the therapeuticagent 30 than a material having fewer pores 42 therein.

In other embodiments, the coating comprises a first coating compositioncomprising a therapeutic agent and a polymer disposed on the surface ofa medical device and a second coating composition comprising a metallicmaterial disposed on the first coating composition. The second coatingcomposition is substantially free of any polymer. Also, the after thesecond coating composition is disposed on the first coating composition,the second coating composition comprises a plurality of pores thatextend from the outer surface of the first composition to the outersurface of the second coating composition.

FIG. 2 shows a cross-sectional view of another embodiment of a coatingdisposed on at least a portion of a surface of a medical device. In thisembodiment medical device 10 has a surface 12 and a coating 20. Coating20 has a first coating composition 22 comprising a therapeutic agent 30and a polymer 32 disposed on the surface 12 of the medical device 10.The first coating composition 22 when disposed on the surface 12 has anouter surface 22 a. A second coating composition 24 comprising ametallic material 40 is disposed on at least a portion of the firstcoating composition 22. As shown in FIG. 2, the second coatingcomposition 24, when applied on the first coating composition 22, has anouter surface 24 a and a plurality of pores 42. Like FIG. 1, the pores42 extend from the outer surface 22 a of the first coating composition22 to the outer surface 24 a of the second coating composition 24.

As shown in FIGS. 1 and 2, the first and second coating compositions canbe disposed on the surface of a medical device in the form of layers.The coating can comprise one layer of each of the first and secondcoating compositions, as shown in FIGS. 1 and 2. However, more than onelayer of each of the first and second coating compositions can bedisposed on the surface of a medical device.

In other embodiments, the first coating composition disposed on thesurface of medical device in a layer can have a thickness of about 1micron to about 30 microns or about 1 micron to about 10 microns.Preferably, the first coating composition can have a thickness of about3 microns to about 15 microns or about 0.8 microns to about 3.5 microns.In some instances, a relatively thicker layer may be preferred toincorporate greater amounts of the therapeutic agent. In addition, arelatively thicker layer may allow a greater amount of a therapeuticagent to be released over time.

The second coating composition comprising a metallic material, whendisposed on the first coating composition, can have a thickness of about0.1 micron to about 30 microns. Preferably, the second coatingcomposition comprising a metallic material, when disposed on the firstcoating composition, can have a thickness of about 1 micron to about 10microns. In addition, a relatively thicker film may allow thetherapeutic agent to be released more slowly over time.

For the second coating composition, suitable metallic materials includeany material that includes a metal such as, but not limited to metals,metal alloys or metal oxides that are biocompatible. Such metallicmaterials include, but are not limited to, metals and alloys based ontitanium (such as nitinol, nickel titanium alloys, thermo-memory alloymaterials); stainless steel; tantalum; tungsten; molybdenum;nickel-chrome; or certain cobalt alloys including cobalt-chromium-nickelalloys such as Elgiloy® and Phynox®; PERSS (Platinum EnRiched StainlessSteel) and Niobium. Metallic materials also include clad compositefilaments, such as those disclosed in WO 94/16646. Preferred, metallicmaterials include, platinum enriched stainless steel and zirconium andniobium alloys. Additionally, combinations of more than one metal oralloy can be used in the coatings of the present invention.

In some embodiments, the metallic material comprises at least 5%, atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 95%, atleast 97%, at least 99% or more by weight of the second coatingcomposition. Preferably, the metallic material is about 1% to about 80%by weight of the first coating composition. More preferably, themetallic material is about 50% to about 100% by weight of the secondcoating composition.

The second coating composition is substantially free of any polymer,i.e. contains less than about 50% of polymer by weight of the secondcoating composition. In some embodiments, the second coating compositionis free of any polymer.

The coating can be disposed on the entire surface of the medical deviceor the coating can be disposed on a portion of the medical device. Forexample, if a medical device, such as a stent, that has an abluminalsurface, i.e. the surface that contacts the body tissue, and anadluminal surface i.e. the surface that faces the lumen of the stent andis opposite the abluminal surface, the coating can be disposed on theabluminal surface while the adluminal surface can be free of thecoating.

FIG. 3 shows an example of a portion of a stent that is suitable for usein the present invention that has an abluminal and adluminal surface.FIG. 3 shows an implantable intravascular stent 50 comprising a sidewall52 which comprises a plurality of struts 60 and openings 55 in thesidewall 52. Generally, the openings 55 are disposed between adjacentstruts 60. Also, the sidewall 52 may have a first sidewall surface 56and an opposing second sidewall surface, which is not shown in FIG. 3.The first sidewall surface 56 can be an abluminal surface or outersidewall surface, which faces the body tissue when the stent isimplanted, or an adluminal surface or inner sidewall surface, whichfaces away from the body tissue. Likewise, the second sidewall surfacecan be an abluminal surface or an adluminal surface.

In certain embodiments, when the medical device, such as a stent, has asidewall structure with openings therein it is preferable that the firstcoating composition and second coating composition disposed on thesurface medical device, conform to the sidewall structure of the medicaldevice so that the openings in the sidewall structure are preserved,e.g. the openings are not entirely or partially occluded with coatingmaterial.

FIG. 4 shows a cross-sectional view of an intravascular stent 100 thatcomprises a plurality of struts 105 and a lumen 130. The struts 105 eachcomprise an abluminal surface 110, which faces away from the lumen 130,and contact the body tissue, such as a blood vessel, when the stent 100is implanted. The struts 105 each comprise an adluminal surface 120,which faces the lumen 130 when the stent 100 is implanted.

FIGS. 4 a and 4 b show two embodiments where the struts of the stent 100of FIG. 4 include the coatings of the present invention. In particular,FIG. 4 a shows an embodiment where the first coating composition 22 isdisposed on at least a portion of the abluminal surface 12 a and theadluminal surface 12 b of a strut 105. The first coating composition 22comprises a therapeutic agent 30 and optionally a polymer. A secondcoating composition 24 comprising a metallic material 40 is disposed onat least a portion of the first coating composition 22 that is disposedon the abluminal surface 12 a and the adluminal surface 12 b of thestrut 105. The second coating composition 24 when applied on the firstcoating composition 22 has an outer surface 24 a and a plurality ofpores 42. The pores 42 extend from the outer surface 22 a of the firstcoating composition 22 to the outer surface 24 a of the second coatingcomposition 24.

FIG. 4 b shows an embodiment where the first coating composition 22 isdisposed on at least a portion of the abluminal surface 12 a and theadluminal surface 12 b of a strut 105. The first coating composition 22comprises a therapeutic agent 30 and optionally a polymer. A secondcoating composition 24 comprising a metallic material 40 is disposedonly on at least a portion of the first coating composition 22 that isdisposed on the abluminal surface 12 a. The second coating composition24 is not disposed on the portion of the first coating composition 22that is disposed on the adluminal surface 12 b of the strut 105. LikeFIG. 4 a, the second coating composition 24 when applied on the firstcoating composition 22 has an outer surface 24 a and a plurality ofpores 42. The pores 42 extend from the outer surface 22 a of the firstcoating composition 22 to the outer surface 24 a of the second coatingcomposition 24.

The second coating composition can be disposed completely over the firstcoating composition or the second coating composition can be disposedover a portion of the first coating composition. Additionally the secondcoating composition can be disposed on the first coating composition inany configuration such as, rings, bands, stripes or dots.

FIG. 5 shows a perspective view of a round stent strut 200 comprising asurface 205 and a coating 210. Coating 210 is disposed on surface 205.Coating 210 comprises a first coating composition 215 comprising atherapeutic agent 220 and a polymer 225 disposed on surface 205 and asecond coating composition 230 comprising a metallic material 240disposed on the first coating composition 215. In this embodiment, thesecond coating composition 230 is disposed on the first coatingcomposition 215 in the configuration of rings 250.

FIG. 6 shows a perspective view of a square-shaped stent strut 300comprising a surface 305 and a coating 310. Coating 310 is disposed onsurface 305. Coating 310 comprises a first coating composition 315comprising a therapeutic agent 320 and a polymer 325 disposed on surface305 and a second coating composition 330 comprising a metallic material340 with pores as discussed above, disposed on the first coatingcomposition 315. In this embodiment, the second coating composition 330is disposed on the first coating composition 315 in the configuration ofbands 350.

In another embodiment, second coating composition can be in theconfiguration of parallel bands or stripes. FIG. 7 shows a stent strut400 comprising a surface 405 and a coating 410. Coating 410 is disposedon surface 405. Coating 410 comprises a first coating composition 415comprising a therapeutic agent 420 and a polymer 425 disposed on surface405 and a second coating composition 430 comprising a metallic material440 with pores as discussed above, disposed on the first coatingcomposition 415. In this embodiment, the second coating composition 430is disposed on the first coating composition 415 in the configuration ofparallel bands or stripes 450.

FIG. 8 shows a stent strut 500 comprising a surface 505 and a coating510. Coating 510 is disposed on surface 505. Coating 510 comprises afirst coating composition 515 comprising a therapeutic agent 520 and apolymer 525 disposed on surface 505 and a second coating composition 530comprising a metallic material 540 with pores as discussed above,disposed on the first coating composition 515. In this embodiment, thesecond coating composition 530 is disposed on the first coatingcomposition 515 in the configuration of wavy bands or stripes 550.

FIGS. 5-8 show some examples of configurations of the first coatingcomposition and the second coating composition; however, otherconfigurations of the first coating composition and the second coatingcomposition can be used.

Also, in some embodiments, the second coating composition can bedisposed on the first coating composition, as well as, the surface ofthe medical device. FIG. 9 shows a cross-section view of anotherembodiment of a coating disposed on at least a portion of a medicaldevice. In this embodiment medical device 600 has a surface 605 andcoating 610 is disposed on surface 605 of medical device 600. Coating610 includes a first coating composition 615 comprising a therapeuticagent 620 and optionally a polymer that is disposed on portions of thesurface 605 of medical device 600. A second coating composition 630comprising a metallic material 640 is disposed on the first coatingcomposition 615, as well as on at least a portion of the surface 605 ofthe medical device 600. As shown in FIG. 9, the second coatingcomposition 630 when disposed on the first coating composition 615 hasan outer surface 630 a and a plurality of pores 642. The pores 642extend from the outer surface 615 a of the first coating composition 615to the outer surface 630 a of the second coating composition 630.

In still other embodiments, the coating can comprise a first coatingcomposition comprising a therapeutic agent and optionally a polymerdisposed on the surface of a medical device, such as an implantable,intravascular stent and second coating composition comprising a metallicmaterial also disposed on the surface of the medical device. FIG. 10shows a cross-sectional view of an embodiment of a coating disposed onat least a portion of a medical device. In this embodiment medicaldevice 700 has a surface 705 and a coating 710 disposed on the surface705 of the medical device 700. Coating 710 includes a first coatingcomposition 715 comprising a therapeutic agent 720 and optionally apolymer disposed on the surface 705 of the medical device 700. Thecoating 710 also includes a second coating composition 730 comprising ametallic material 740 that is also disposed on the surface 705 of themedical device 700. The second coating composition 730 is substantiallyfree of any polymer. In some embodiments, the second coating composition730 when applied to the surface 705 can but need not include the poresdescribed above. As shown in FIG. 10, when disposed on the surface 705,both the first coating composition 715 and second coating composition730 can have the same thickness, h.

Alternatively, as shown in FIG. 11, the thicknesses of the first coatingcomposition 715 and the second coating composition 730 when disposed onthe surface 705 of the medical device 700 can be different. As shown inFIG. 11, coating 710 has a first coating composition 715 comprising atherapeutic agent 720 and a polymer 725 and a second coating composition730 comprising a metallic material 740. When the first coatingcomposition 715 comprises a polymer 725, it may be preferable for thethickness, x, of the second coating composition 730 to be greater thanthe thickness, y, of the first coating composition 715. Having thethickness x of the second coating composition 730, which issubstantially free of any polymer, greater than that of the thickness yof the first coating composition prevents the polymer 725 in the firstcoating composition 715 from contacting the body lumen. This mayeliminate possible adverse effects to the body lumen caused by contactwith a polymer.

A. Medical Devices

Suitable medical devices for the present invention include, but are notlimited to, stents, surgical staples, cochlear implants, embolic coils,catheters, such as central venous catheters and arterial catheters,guidewires, cannulas, cardiac pacemaker leads or lead tips, cardiacdefibrillator leads or lead tips, implantable vascular access ports,blood storage bags, blood tubing, vascular or other grafts, intra-aorticballoon pumps, heart valves, cardiovascular sutures, total artificialhearts and ventricular assist pumps, extra-corporeal devices such asblood oxygenators, blood filters, hemodialysis units, hemoperfusionunits or plasmapheresis units.

Medical devices which are particularly suitable for the presentinvention include any stent for medical purposes, which are known to theskilled artisan. Suitable stents include, for example, vascular stentssuch as self-expanding stents, balloon expandable stents and sheetdeployable stents. Examples of self-expanding stents are illustrated inU.S. Pat. Nos. 4,655,771 and 4,954,126 issued to Wallsten and U.S. Pat.No. 5,061,275 issued to Wallsten et al. Examples of appropriateballoon-expandable stents are shown in U.S. Pat. No. 5,449,373 issued toPinchasik et al. In preferred embodiments, the stent suitable for thepresent invention is an Express stent. More preferably, the Expressstent is an Express™ stent or an Express2™ stent (Boston Scientific,Inc. Natick, Mass.).

The framework of the suitable stents may be formed through variousmethods as known in the art. The framework may be welded, molded, lasercut, electro-formed, or consist of filaments or fibers which are woundor braided together in order to form a continuous structure.

Medical devices that are suitable for the present invention may befabricated from metallic, ceramic, polymeric or composite materials or acombination thereof. Preferably, the materials are biocompatible.Metallic material is more preferable. Suitable metallic materialsinclude metals and alloys based on titanium (such as nitinol, nickeltitanium alloys, thermo-memory alloy materials); stainless steel;tantalum, nickel-chrome; or certain cobalt alloys includingcobalt-chromium-nickel alloys such as Elgiloy® and Phynox®; PERSS(Platinum EnRiched Stainless Steel) and Niobium. Metallic materials alsoinclude clad composite filaments, such as those disclosed in WO94/16646. Preferred, metallic materials include, platinum enrichedstainless steel and zirconium and niobium alloys.

Suitable ceramic materials include, but are not limited to, oxides,carbides, or nitrides of the transition elements such as titanium,hafnium, iridium, chromium, aluminum, and zirconium. Silicon basedmaterials, such as silica, may also be used.

Suitable polymeric materials for forming the medical devices may bebiostable. Also, the polymeric material may be biodegradable. Suitablepolymeric materials include, but are not limited to, styrene isobutylenecopolymers, polyetheroxides, polyvinyl alcohol, polyglycolic acid,polylactic acid, polyamides, poly-2-hydroxy-butyrate, polycaprolactone,poly(lactic-co-clycolic)acid, and Teflon.

Polymeric materials may be used for forming the medical device in thepresent invention include without limitation isobutylene-based polymers,polystyrene-based polymers, polyacrylates, and polyacrylate derivatives,vinyl acetate-based polymers and its copolymers, polyurethane and itscopolymers, silicone and its copolymers, ethylene vinyl-acetate,polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride,polyolefins, cellulosics, polyamides, polyesters, polysulfones,polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrenecopolymers, acrylics, polylactic acid, polyglycolic acid,polycaprolactone, polylactic acid-polyethylene oxide copolymers,cellulose, collagens, and chitins.

Other polymers that are useful as materials for medical devices includewithout limitation dacron polyester, poly(ethylene terephthalate),polycarbonate, polymethylmethacrylate, polypropylene, polyalkyleneoxalates, polyvinylchloride, polyurethanes, polysiloxanes, nylons,poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes,poly(amino acids), ethylene glycol I dimethacrylate, poly(methylmethacrylate), poly(2-hydroxyethyl methacrylate),polytetrafluoroethylene poly(HEMA), polyhydroxyalkanoates,polytetrafluorethylene, polycarbonate, poly(glycolide-lactide)co-polymer, polylactic acid, poly(γ-caprolactone),poly(γ-hydroxybutyrate), polydioxanone, poly(γ-ethyl glutamate),polyiminocarbonates, poly(ortho ester), polyanhydrides, alginate,dextran, chitin, cotton, polyglycolic acid, polyurethane, or derivatizedversions thereof, i.e., polymers which have been modified to include,for example, attachment sites or cross-linking groups, e.g., RGD, inwhich the polymers retain their structural integrity while allowing forattachment of cells and molecules, such as proteins, nucleic acids, andthe like.

Medical devices may also be made with non-polymeric materials. Examplesof useful non-polymeric materials include sterols such as cholesterol,stigmasterol, β-sitosterol, and estradiol; cholesteryl esters such ascholesteryl stearate; C₁₂-C₂₄ fatty acids such as lauric acid, myristicacid, palmitic acid, stearic acid, arachidic acid, behenic acid, andlignoceric acid; C₁₈-C₃₆ mono-, di- and triacylglycerides such asglyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate,glyceryl monodocosanoate, glyceryl monomyristate, glycerylmonodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryldimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryltrimyristate, glyceryl tridecenoate, glycerol tristearate and mixturesthereof; sucrose fatty acid esters such as sucrose distearate andsucrose palmitate; sorbitan fatty acid esters such as sorbitanmonostearate, sorbitan monopalmitate and sorbitan tristearate; C₁₆-C₁₈fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol,and cetostearyl alcohol; esters of fatty alcohols and fatty acids suchas cetyl palmitate and cetearyl palmitate; anhydrides of fatty acidssuch as stearic anhydride; phospholipids including phosphatidylcholine(lecithin), phosphatidylserine, phosphatidylethanolamine,phosphatidylinositol, and lysoderivatives thereof; sphingosine andderivatives thereof; sphingomyelins such as stearyl, palmitoyl, andtricosanyl sphingomyelins; ceramides such as stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohols; andcombinations and mixtures thereof. Non-polymeric materials may alsoinclude biomaterials such as stem sells, which can be seeded into themedical device prior to implantation. Preferred non-polymeric materialsinclude cholesterol, glyceryl monostearate, glycerol tristearate,stearic acid, stearic anhydride, glyceryl monooleate, glycerylmonolinoleate, and acetylated monoglycerides.

B. Therapeutic Agents

The term “therapeutic agent” as used in the present inventionencompasses drugs, genetic materials, and biological materials and canbe used interchangeably with “biologically active material”. In oneembodiment, the therapeutic agent is an anti-restenotic agent. In otherembodiments, the therapeutic agent inhibits smooth muscle cellproliferation, contraction, migration or hyperactivity. Non-limitingexamples of suitable therapeutic agent include heparin, heparinderivatives, urokinase, dextrophenylalanine proline argininechloromethylketone (PPack), enoxaprin, angiopeptin, hirudin,acetylsalicylic acid, tacrolimus, everolimus, zotarolimus, rapamycin(sirolimus), pimecrolimus, amlodipine, doxazosin, glucocorticoids,betamethasone, dexamethasone, prednisolone, corticosterone, budesonide,sulfasalazine, rosiglitazone, mycophenolic acid, mesalamine, paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,methotrexate, azathioprine, adriamycin, mutamycin, endostatin,angiostatin, thymidine kinase inhibitors, cladribine, lidocaine,bupivacaine, ropivacaine, D-Phe-Pro-Arg chloromethyl ketone, plateletreceptor antagonists, anti-thrombin antibodies, anti-platelet receptorantibodies, aspirin, dipyridamole, protamine, hirudin, prostaglandininhibitors, platelet inhibitors, trapidil, liprostin, tick antiplateletpeptides, 5-azacytidine, vascular endothelial growth factors, growthfactor receptors, transcriptional activators, translational promoters,antiproliferative agents, growth factor inhibitors, growth factorreceptor antagonists, transcriptional repressors, translationalrepressors, replication inhibitors, inhibitory antibodies, antibodiesdirected against growth factors, bifunctional molecules consisting of agrowth factor and a cytotoxin, bifunctional molecules consisting of anantibody and a cytotoxin, cholesterol lowering agents, vasodilatingagents, agents which interfere with endogenous vasoactive mechanisms,antioxidants, probucol, antibiotic agents, penicillin, cefoxitin,oxacillin, tobranycin, angiogenic substances, fibroblast growth factors,estrogen, estradiol (E2), estriol (E3), 17-beta estradiol, digoxin, betablockers, captopril, enalopril, statins, steroids, vitamins, paclitaxel(as well as its derivatives, analogs or paclitaxel bound to proteins,e.g. Abraxane™) 2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine,2′-glutaryl-taxol, 2′-glutaryl-taxol triethanolamine salt, 2′-O-esterwith N-(dimethylaminoethyl)glutamine, 2′-O-ester withN-(dimethylaminoethyl)glutamide hydrochloride salt, nitroglycerin,nitrous oxides, nitric oxides, antibiotics, aspirins, digitalis,estrogen, estradiol and glycosides. In one embodiment, the therapeuticagent is a smooth muscle cell inhibitor or antibiotic. In a preferredembodiment, the therapeutic agent is taxol (e.g., Taxol®), or itsanalogs or derivatives. In another preferred embodiment, the therapeuticagent is paclitaxel, or its analogs or derivatives. In yet anotherpreferred embodiment, the therapeutic agent is an antibiotic such aserythromycin, amphotericin, rapamycin, adriamycin, etc.

The term “genetic materials” means DNA or RNA, including, withoutlimitation, of DNA/RNA encoding a useful protein stated below, intendedto be inserted into a human body including viral vectors and non-viralvectors.

The term “biological materials” include cells, yeasts, bacteria,proteins, peptides, cytokines and hormones. Examples for peptides andproteins include vascular endothelial growth factor (VEGF), transforminggrowth factor (TGF), fibroblast growth factor (FGF), epidermal growthfactor (EGF), cartilage growth factor (CGF), nerve growth factor (NGF),keratinocyte growth factor (KGF), skeletal growth factor (SGF),osteoblast-derived growth factor (BDGF), hepatocyte growth factor (HGF),insulin-like growth factor (IGF), cytokine growth factors (CGF),platelet-derived growth factor (PDGF), hypoxia inducible factor-1(HIF-1), stem cell derived factor (SDF), stem cell factor (SCF),endothelial cell growth supplement (ECGS), granulocyte macrophage colonystimulating factor (GM-CSF), growth differentiation factor (GDF),integrin modulating factor (IMF), calmodulin (CaM), thymidine kinase(TK), tumor necrosis factor (TNF), growth hormone (GH), bone morphogenicprotein (BMP) (e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7(PO-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-14, BMP-15, BMP-16,etc.), matrix metalloproteinase (MMP), tissue inhibitor of matrixmetalloproteinase (TIMP), cytokines, interleukin (e.g., IL-1, IL-2,IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15,etc.), lymphokines, interferon, integrin, collagen (all types), elastin,fibrillins, fibronectin, vitronectin, laminin, glycosaminoglycans,proteoglycans, transferrin, cytotactin, cell binding domains (e.g.,RGD), and tenascin. Currently preferred BMP's are BMP-2, BMP-3, BMP-4,BMP-5, BMP-6, BMP-7. These dimeric proteins can be provided ashomodimers, heterodimers, or combinations thereof, alone or togetherwith other molecules. Cells can be of human origin (autologous orallogeneic) or from an animal source (xenogeneic), geneticallyengineered, if desired, to deliver proteins of interest at thetransplant site. The delivery media can be formulated as needed tomaintain cell function and viability. Cells include progenitor cells(e.g., endothelial progenitor cells), stem cells (e.g., mesenchymal,hematopoietic, neuronal), stromal cells, parenchymal cells,undifferentiated cells, fibroblasts, macrophage, and satellite cells.

Other non-genetic therapeutic agents include:

-   -   anti-thrombogenic agents such as heparin, heparin derivatives,        urokinase, and PPack (dextrophenylalanine proline arginine        chloromethylketone);    -   anti-proliferative agents such as enoxaprin, angiopeptin, or        monoclonal antibodies capable of blocking smooth muscle cell        proliferation, hirudin, acetylsalicylic acid, tacrolimus,        everolimus, amlodipine and doxazosin;    -   anti-inflammatory agents such as glucocorticoids, betamethasone,        dexamethasone, prednisolone, corticosterone, budesonide,        estrogen, sulfasalazine, rosiglitazone, mycophenolic acid and        mesalamine;    -   anti-neoplastic/anti-proliferative/anti-miotic agents such as        paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,        epothilones, methotrexate, azathioprine, adriamycin and        mutamycin; endostatin, angiostatin and thymidine kinase        inhibitors, cladribine, taxol and its analogs or derivatives;    -   anesthetic agents such as lidocaine, bupivacaine, and        ropivacaine;    -   anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an        RGD peptide-containing compound, heparin, antithrombin        compounds, platelet receptor antagonists, anti-thrombin        antibodies, anti-platelet receptor antibodies, aspirin (aspirin        is also classified as an analgesic, antipyretic and        anti-inflammatory drug), dipyridamole, protamine, hirudin,        prostaglandin inhibitors, platelet inhibitors, antiplatelet        agents such as trapidil or liprostin and tick antiplatelet        peptides;    -   DNA demethylating drugs such as 5-azacytidine, which is also        categorized as a RNA or DNA metabolite that inhibit cell growth        and induce apoptosis in certain cancer cells;    -   vascular cell growth promoters such as growth factors, vascular        endothelial growth factors (VEGF, all types including VEGF-2),        growth factor receptors, transcriptional activators, and        translational promoters;    -   vascular cell growth inhibitors such as anti-proliferative        agents, growth factor inhibitors, growth factor receptor        antagonists, transcriptional repressors, translational        repressors, replication inhibitors, inhibitory antibodies,        antibodies directed against growth factors, bifunctional        molecules consisting of a growth factor and a cytotoxin,        bifunctional molecules consisting of an antibody and a        cytotoxin;    -   cholesterol-lowering agents, vasodilating agents, and agents        which interfere with endogenous vasoactive mechanisms;    -   anti-oxidants, such as probucol;    -   antibiotic agents, such as penicillin, cefoxitin, oxacillin,        tobranycin, rapamycin (sirolimus);    -   angiogenic substances, such as acidic and basic fibroblast        growth factors, estrogen including estradiol (E2), estriol (E3)        and 17-beta estradiol;    -   drugs for heart failure, such as digoxin, beta-blockers,        angiotensin-converting enzyme (ACE) inhibitors including        captopril and enalopril, statins and related compounds; and    -   macrolides such as sirolimus, everolimus or zotarolimus.

Preferred biological materials include anti-proliferative drugs such assteroids, vitamins, and restenosis-inhibiting agents. Preferredrestenosis-inhibiting agents include microtubule stabilizing agents suchas Taxol®, paclitaxel (i.e., paclitaxel, paclitaxel analogs, orpaclitaxel derivatives, paclitaxel conjugates and mixtures thereof). Forexample, derivatives suitable for use in the present invention include2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol,2′-glutaryl-taxol triethanolamine salt, 2′-O-ester withN-(dimethylaminoethyl) glutamine, paclitaxel 2-N-methypyridiniummesylate, and 2′-O-ester with N-(dimethylaminoethyl) glutamidehydrochloride salt. Paclitaxel conjugates suitable for use in thepresent invention include, paclitaxel conjugated with docosahexanoicacid (DHA), paclitaxel conjugated with a polyglutimate (PG) polymer andpaclitaxel poliglumex.

Other suitable therapeutic agents include tacrolimus; halofuginone;inhibitors of HSP90 heat shock proteins such as geldanamycin;microtubule stabilizing agents such as epothilone D; phosphodiesteraseinhibitors such as cliostazole; Barkct inhibitors; phospholambaninhibitors; and Serca 2 gene/proteins.

Other preferred therapeutic agents include nitroglycerin, nitrousoxides, nitric oxides, aspirins, digitalis, estrogen derivatives such asestradiol and glycosides.

In one embodiment, the therapeutic agent is capable of altering thecellular metabolism or inhibiting a cell activity, such as proteinsynthesis, DNA synthesis, spindle fiber formation, cellularproliferation, cell migration, microtubule formation, microfilamentformation, extracellular matrix synthesis, extracellular matrixsecretion, or increase in cell volume. In another embodiment, thetherapeutic agent is capable of inhibiting cell proliferation and/ormigration.

In certain embodiments, the therapeutic agents for use in the medicaldevices of the present invention can be synthesized by methods wellknown to one skilled in the art. Alternatively, the therapeutic agentscan be purchased from chemical and pharmaceutical companies.

In some embodiments, the therapeutic agent comprises at least 1%, atleast 5%, at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, at least 97%, at least 99% or more by weight of the coating.When the coating includes a therapeutic agent without a polymer thetherapeutic agent is preferably about 90% to about 100% by weight of thecoating. When the coating includes a therapeutic agent and a polymer thetherapeutic agent is preferably about 1% to about 90% by weight of thecoating. Additionally, a combination of therapeutic agents can be usedin the coatings of the present invention.

C. Polymers

Polymers suitable for use, optionally, in the coatings preferably areones that are biocompatible; however, non-biocompatible polymers can beused. Examples of such polymers include, but not limited to,polyurethanes, polyisobutylene and its copolymers, silicones, andpolyesters. Other suitable polymers include polyolefins,polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers andcopolymers, vinyl halide polymers and copolymers such as polyvinylchloride, polyvinyl ethers such as polyvinyl methyl ether,polyvinylidene halides such as polyvinylidene fluoride andpolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics such as polystyrene, polyvinyl esters such as polyvinylacetate; copolymers of vinyl monomers, copolymers of vinyl monomers andolefins such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetatecopolymers, polyamides such as Nylon 66 and polycaprolactone, alkydresins, polycarbonates, polyoxyethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, carboxymethylcellulose, collagens, chitins, polylactic acid, polyglycolic acid, andpolylactic acid-polyethylene oxide copolymers.

When the polymer is being applied to a part of the medical device, suchas a stent, which undergoes mechanical challenges, e.g. expansion andcontraction, the polymers are preferably selected from elastomericpolymers such as silicones (e.g. polysiloxanes and substitutedpolysiloxanes), polyurethanes, thermoplastic elastomers, ethylene vinylacetate copolymers, polyolefin elastomers, and EPDM rubbers. The polymeris selected to allow the coating to better adhere to the surface of thestrut when the stent is subjected to forces or stress. Furthermore,although the coating can be formed by using a single type of polymer,various combinations of polymers can be employed.

Examples of suitable hydrophobic polymers or monomers include, but notlimited to, polyolefins, such as polyethylene, polypropylene,poly(1-butene), poly(2-butene), poly(1-pentene), poly(2-pentene),poly(3-methyl-1-pentene), poly(4-methyl-1-pentene), poly(isoprene),poly(4-methyl-1-pentene), ethylene-propylene copolymers,ethylene-propylene-hexadiene copolymers, ethylene-vinyl acetatecopolymers, blends of two or more polyolefins and random and blockcopolymers prepared from two or more different unsaturated monomers;styrene polymers, such as poly(styrene), poly(2-methylstyrene),styrene-acrylonitrile copolymers having less than about 20 mole-percentacrylonitrile, and styrene-2,2,3,3,-tetrafluoropropyl methacrylatecopolymers; halogenated hydrocarbon polymers, such aspoly(chlorotrifluoroethylene),chlorotrifluoroethylene-tetrafluoroethylene copolymers,poly(hexafluoropropylene), poly(tetrafluoroethylene),tetrafluoroethylene, tetrafluoroethylene-ethylene copolymers,poly(trifluoroethylene), poly(vinyl fluoride), and poly(vinylidenefluoride); vinyl polymers, such as poly(vinyl butyrate), poly(vinyldecanoate), poly(vinyl dodecanoate), poly(vinyl hexadecanoate),poly(vinyl hexanoate), poly(vinyl propionate), poly(vinyl octanoate),poly(heptafluoroisopropoxyethylene),poly(heptafluoroisopropoxy-propylene), and poly(methacrylonitrile);acrylic polymers, such as poly(n-butyl acetate), poly(ethyl acrylate),poly(1-chlorodifluoromethyl)tetrafluoroethyl acrylate, polydi(chlorofluoromethyl)fluoromethyl acrylate,poly(1,1-dihydroheptafluorobutyl acrylate),poly(1,1-dihydropentafluoroisopropyl acrylate),poly(1,1-dihydro-pentadecafluorooctyl acrylate),poly(heptafluoroisopropyl acrylate), poly5-(heptafluoroisopropoxy)pentyl acrylate, poly11-(heptafluoroisopropoxy)undecyl acrylate, poly2-(heptafluoropropoxy)ethyl acrylate, and poly(nonafluoroisobutylacrylate); methacrylic polymers, such as poly(benzyl methacrylate),poly(n-butyl methacrylate), poly(isobutyl methacrylate), poly(t-butylmethacrylate), poly(t-butylaminoethyl methacrylate), poly(dodecylmethacrylate), poly(ethyl methacrylate), poly(2-ethylhexylmethacrylate), poly(n-hexyl methacrylate), poly(phenyl methacrylate),poly(n-propyl methacrylate), poly(octadecyl methacrylate),poly(1,1-dihydropentadecafluorooctyl methacrylate),poly(heptafluoroisopropyl methacrylate), poly(heptadecafluorooctylmethacrylate), poly(1-hydrotetrafluoroethyl methacrylate),poly(1,1-dihydrotetrafluoropropyl methacrylate),poly(1-hydrohexafluoroisopropyl methacrylate), andpoly(t-nonafluorobutyl methacrylate); polyesters, such a poly(ethyleneterephthalate) and poly(butylene terephthalate); condensation typepolymers such as and polyurethanes and siloxane-urethane copolymers;polyorganosiloxanes, i.e., polymeric materials characterized byrepeating siloxane groups, represented by RaSiO_(4-a/2), where R is amonovalent substituted or unsubstituted hydrocarbon radical and thevalue of a is 1 or 2; and naturally occurring hydrophobic polymers suchas rubber.

Examples of suitable hydrophilic polymers or monomers include, but notlimited to; (meth)acrylic acid, or alkaline metal or ammonium saltsthereof; (meth)acrylamide; (meth)acrylonitrile; those polymers to whichunsaturated dibasic, such as maleic acid and fumaric acid or half estersof these unsaturated dibasic acids, or alkaline metal or ammonium saltsof these dibasic adds or half esters, is added; those polymers to whichunsaturated sulfonic, such as 2-acrylamido-2-methylpropanesulfonic,2-(meth)acryloylethanesulfonic acid, or alkaline metal or ammonium saltsthereof, is added; and 2-hydroxyethyl(meth)acrylate and2-hydroxypropyl(meth)acrylate.

Polyvinyl alcohol is also an example of hydrophilic polymer. Polyvinylalcohol may contain a plurality of hydrophilic groups such as hydroxyl,amido, carboxyl, amino, ammonium or sulfonyl (—SO₃). Hydrophilicpolymers also include, but are not limited to, starch, polysaccharidesand related cellulosic polymers; polyalkylene glycols and oxides such asthe polyethylene oxides; polymerized ethylenically unsaturatedcarboxylic acids such as acrylic, mathacrylic and maleic acids andpartial esters derived from these acids and polyhydric alcohols such asthe alkylene glycols; homopolymers and copolymers derived fromacrylamide; and homopolymers and copolymers of vinylpyrrolidone.

Other suitable polymers include without limitation: polyurethanes,silicones (e.g., polysiloxanes and substituted polysiloxanes), andpolyesters, styrene-isobutylene-copolymers. Other polymers which can beused include ones that can be dissolved and cured or polymerized on themedical device or polymers having relatively low melting points that canbe blended with therapeutic agents. Additional suitable polymersinclude, but are not limited to, thermoplastic elastomers in general,polyolefins, polyisobutylene, ethylene-alphaolefin copolymers, acrylicpolymers and copolymers, vinyl halide polymers and copolymers such aspolyvinyl chloride, polyvinyl ethers such as polyvinyl methyl ether,polyvinylidene halides such as polyvinylidene fluoride andpolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics such as polystyrene, polyvinyl esters such as polyvinylacetate, copolymers of vinyl monomers, copolymers of vinyl monomers andolefins such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS (acrylonitrile-butadiene-styrene)resins, ethylene-vinyl acetate copolymers, polyamides such as Nylon 66and polycaprolactone, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, polyether block amides, epoxy resins,rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, collagens,chitins, polylactic acid, polyglycolic acid, polylacticacid-polyethylene oxide copolymers, EPDM (ethylene-propylene-diene)rubbers, fluoropolymers, fluorosilicones, polyethylene glycol,polysaccharides, phospholipids, and combinations of the foregoing.

In certain embodiments block-copolymers are preferred for their abilityto help create mesostructured and/or mesoporous coatings. In certainembodiments preferred polymers include, but are not limited to, apolyether, Nylon and polyether copolymers such as PEBAX, a polystyrenecopolymer, a polyurethane, an ethylene vinyl acetate copolymer, apolyethylene glycol, a fluoropolymer, a polyaniline, a polythiophene, apolypyrrole, a maleated block copolymer, a polymethylmethacrylate, apolyethylenetheraphtalate or a combination thereof.

In some embodiments, when the first coating composition includes apolymer, the polymer comprises at least 5%, at least 10%, at least 20%,at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, at least 97%, at least 99% ormore by weight of the coating. Preferably, the polymer is about 1% toabout 80% by weight of the first coating composition. More preferably,the polymer is about 60% to about 92% by weight of the first coatingcomposition. Additionally, a combination of polymers can be used in thefirst coating composition of the present invention.

D. Methods of Making Coatings

The present invention also relates to methods of making a medical devicecomprising a coating, wherein the coating comprises a first coatingcomposition comprising a therapeutic agent and a second coatingcomposition comprising a metallic material. Optionally the first coatingcomposition can further comprise a polymer. In certain embodiments, themethod comprises (a) providing a medical device having a surface, (b)disposing on at least a portion of the surface a first coatingcomposition comprising a therapeutic agent; and (c) disposing on atleast a portion of the first coating composition, a second coatingcomposition comprising a metallic material and that is substantiallyfree of any polymer.

In other embodiments, the method of the present invention comprises (a)providing a medical device having a surface, (b) disposing on at least aportion of the surface a first coating composition comprising atherapeutic agent and a polymer; and (c) disposing on at least a portionof the first coating composition, a second coating compositioncomprising a metallic material and that is substantially free of anypolymer.

In such embodiments the first coating composition may be disposed on thesurface of a medical device by any suitable method, such as, but notlimited to, spraying for example by using a conventional nozzle orultrasonic nozzle; dipping; rolling; electrostatic deposition; spincoating; plasma deposition; condensation; electrochemical deposition;electrostatic deposition; evaporation; plasma-vapor deposition;cathodic-arc deposition; sputtering; ion implantation; or use of afluidized bed or a batch process such as, air suspension, pan coating orultrasonic mist spraying.

The first coating composition can be made by dissolving or dispersingthe therapeutic agent solvent to form a solution or suspension and thesolution or suspension can be disposed on the surface of a medicaldevice and the solvent can be removed. Alternatively, if the firstcoating composition includes a polymer, a therapeutic agent and apolymer can be dissolved or dispersed in a solvent to form a solution orsuspension and the solution or suspension can be disposed on the surfaceof a medical device and the solvent can be removed. Also, a therapeuticagent and a polymer may be mixed together until the therapeutic agent isdissolved or dispersed in the polymer and the mixture can then bedisposed of the surface of a medical device.

The second coating composition comprising a metallic material can bedisposed on the first coating composition by any suitable methods, suchas, but not limited to, spraying for example by using a conventionalnozzle or ultrasonic nozzle; dipping; rolling; electrostatic deposition;spin coating; plasma deposition; condensation; electrochemicaldeposition; electrostatic deposition; evaporation; plasma-vapordeposition; cathodic-arc deposition; sputtering; ion implantation; oruse of a fluidized bed or a batch process such as, air suspension, pancoating, ultrasonic mist spraying or thermal spraying.

Prior to deposition, the metallic material in the second coatingcomposition can be placed into a solution or suspension to facilitatedeposition. Solutions can be formed using suitable solvents and metalliccompounds. Suspensions can be formed by mixing metallic powders withsolvents or polymer binders and solvents.

In certain embodiments, the first coating composition can be disposed onat least a portion of the surface of a medical device and then a secondcoating composition can be disposed on at least a portion of the firstcoating composition. In some embodiments, the second coating compositioncomprising a metallic material can be disposed on the first coatingcomposition, as well as, at least a portion of the surface of the firstcoating composition. Alternatively, the second coating compositioncomprising a metallic material can be disposed on at least a portion ofthe surface of the medical device first and then the first coatingcomposition can be disposed on another portion of the surface of themedical device.

Furthermore, pores can be formed or introduced in the second coatingcomposition comprising a metallic material. Such pores can be introducedby any means known in the art. The pores in some instances can becreated by micro-roughing techniques involving the use of reactiveplasmas or ion bombardment electrolyte etching. The pores can also becreated by other methods such as sand blasting, laser etching orchemical etching. In some instances, the pores can be formed bydepositing the second coating composition comprising a metallic materialin a particular manner so that pores form in the metallic material. Forexample, the second coating composition can be made porous by adeposition process such as sputtering and adjusting the depositioncondition. Deposition conditions that can be adjusted or varied include,but are not limited to, chamber pressure, substrate temperature,substrate bias, substrate orientation, sputter rate, or a combinationthereof.

In an alternative method, the pores may be formed using thermal plasmaspraying of a spray composition under certain process parameters thatpromote the formation of pores.

In addition, pores can be formed by a co-deposition technique. In such atechnique the second coating composition comprising a metallic materialis combined with a secondary phase material to form a composition. Thesecondary phase material can be non-metal secondary materials, such as apolymer, that are capable of being leached off, such as polystyrene. Thesecondary phase material can be in the form of particles such as hollowspheres or chopped tubes of various sizes. The size and shape of thepores formed will be determined by the size and shape of the secondaryphase material. For example, if the secondary phase material is in theshape of a sphere, the pores formed will be in the shape of spheres.

In some embodiments, the secondary phase material can be a secondmetallic material. The two metallic materials can form an alloy such asa gold/silver alloy, where gold is the metal used as the metallicmaterial in the second coating composition and silver is the secondaryphase material. Also, the two metals can be in the form of a mixture ora composite. Thus, if two metals are used in the composition, the metalsshould have different chemical or physical properties to facilitateremoval of the metal that is used as the secondary phase material. Forexample, the metal that will be removed should be more electrochemicallyactive, e.g., less corrosion-resistant than the metal used to form theporous coating. In some embodiments, the metal that will be removedshould have a lower melting point than the metal used to form the secondcoating composition. In yet another embodiment, the metal that will beremoved should have a higher vapor pressure than the metal used to formthe coating. Also, in another embodiment, the metal that is removed ismore susceptible to being dissolved in a chosen solvent than the metalused to form the coating.

A composition containing the second coating composition comprising ametallic material and a secondary phase material is applied to thesurface of the medical device. Suitable application methods include butare not limited to, dipping, spraying, painting, electroplating,evaporation, plasma vapor deposition, cathodic arc deposition,sputtering, ion implantation, electrostatically, electroplating,electrochemically, or a combination thereof.

Afterwards, the secondary phase material is removed from the compositionto form a porous second coating composition. For example, the secondaryphase material may be removed from the composition by a dealloyingprocess such as selective dissolution of the secondary phase material.In this method, the composition is exposed to an acid which removes thesecondary phase material. Thus, the metallic material used to form thesecond coating composition is preferably one that will not dissolve whenexposed to the acid, while the secondary phase material is one that willdissolve in the acid. Any suitable acid can be used to remove thesecondary phase material. One of ordinary skill in the art wouldrecognize the appropriate concentration and reaction conditions to use.For example, if the secondary phase material is silver, nitric acid maybe used at a concentration of up to 35% and a temperature up to 120° F.Also, a nitric acid and sulfuric acid mixture (95%/5%) immersion processat 80° F. may be used. The reaction conditions may be varied to vary thegeometry, distribution, and depth of the coating.

Alternatively, the second metal can be removed anodically. For example,when silver is used as the secondary phase material, the silver may beremoved from the composition applied to the surface anodically using adilute nitric acid bath comprising up to 15% nitric acid, wherein theanode is the medical device, and the cathode comprises platinum.Voltages up to 10V DC can be applied across the electrodes. The bathchemistry, temperature, applied voltage, and process time may be variedto vary the geometry, distribution, and depth of the coating.

Furthermore, if the secondary phase material has a lower melting pointthan the metallic material used in the second coating composition, thedevice coated with the composition containing the second coatingcomposition comprising a metallic material and the secondary phasematerial can be heated to a temperature such that the secondary phasematerial becomes a liquid and is removable from the second coatingcomposition. Examples of suitable metals for the second coatingcomposition include one of the higher melting point first metals:platinum, gold, stainless steel, titanium, tantalum, and iridium, incombination with a lower melting point secondary phase material such as:aluminum, barium, and bismuth.

In another embodiment, the secondary phase material has a higher vaporpressure than the second coating composition comprising a metallicmaterial. When the composition applied to the surface of the medicaldevice is heated under vacuum the secondary phase material becomesvaporized and is removed from the second coating composition.

The description contained herein is for purposes of illustration and notfor purposes of limitation. Changes and modifications may be made to theembodiments of the description and still be within the scope of theinvention. Furthermore, obvious changes, modifications or variationswill occur to those skilled in the art. Also, all references cited aboveare incorporated herein, in their entirety, for all purposes related tothis disclosure.

1. An implantable intravascular stent comprising: (a) a stent sidewall structure having a surface; and (b) a coating comprising: (i) a first coating composition comprising a therapeutic agent disposed upon at least a portion of the surface of the stent sidewall structure, wherein the first coating composition when disposed on the portion of the surface of the stent sidewall structure has an outer surface; and (ii) a second coating composition comprising a metallic material disposed on at least a portion of the first coating composition, wherein the second coating composition is substantially free of any polymer when applied to the portion of the first coating composition; and wherein after the second coating composition is applied to the portion of the first coating composition the second coating composition comprises an outer surface and a plurality of pores, in which the pores extend from the outer surface of the first coating composition to the outer surface of the second coating composition.
 2. The stent of claim 1, wherein the second coating composition is disposed on less than the entire outer surface of the first coating composition.
 3. The stent of claim 1, wherein the surface of the stent sidewall structure is an abluminal surface.
 4. The stent of claim 3, wherein the stent sidewall structure further comprises an adluminal surface and wherein the first coating composition is disposed on at least a portion of the adluminal surface.
 5. The stent of claim 4, wherein the adluminal surface is free of the second coating composition.
 6. The stent of claim 4, wherein the second coating composition is disposed on at least a portion of the first coating composition disposed on the adluminal surface.
 7. The stent of claim 1, wherein the stent sidewall structure comprises a plurality of struts each having an abluminal surface and an adluminal surface and wherein the surface of the stent sidewall structure is the abluminal surface of at least one of the struts.
 8. The stent of claim 7, wherein the first coating composition is disposed on at least a portion of the adluminal surface of at least one of the struts.
 9. The stent of claim 8, wherein the adluminal surface of the strut is free of the second coating composition.
 10. The stent of claim 8, wherein the second coating composition is disposed on at least a portion of the first coating composition disposed on the adluminal surface of the strut.
 11. The stent of claim 1, wherein the stent sidewall structure comprises a plurality of openings therein.
 12. The stent of claim 11, wherein the first and second coating compositions conform to the stent sidewall structure to preserve the openings in the stent sidewall structure.
 13. The stent of claim 1, wherein the therapeutic agent comprises an agent that inhibits smooth muscle cell proliferation.
 14. The stent of claim 1, wherein the therapeutic agent comprises an anti-thrombogenic agent, anti-angiogenesis agent, anti-proliferative agent, antibiotic, anti-restenosis agent, growth factor, immunosuppressant or radiochemical.
 15. The stent of claim 1, wherein the therapeutic agent comprises an anti-restenosis agent.
 16. The stent of claim 1, wherein the therapeutic agent comprises paclitaxel.
 17. The stent of claim 1, wherein the therapeutic agent comprises sirolimus, tacrolimus, pimecrolimus, everolimus or zotarolimus.
 18. The stent of claim 1, wherein the metallic material is selected from the group consisting of stainless steel, nickel, titanium, chromium and alloys thereof.
 19. The stent of claim 1, wherein the first coating composition further comprises at least one polymer.
 20. The stent of claim 17, wherein the polymer is selected from the group consisting of styrene-isobutylene copolymer, polylactic acid, poly(methylmethacrylate-butylacrylate-methylmethacrylate).
 21. The stent of claim 1, wherein the first coating composition forms a first layer having a thickness of about 1 to about 30 microns.
 22. The stent of claim 1, wherein the second coating composition forms a second layer having a thickness of about 0.1 to about 50 microns.
 23. An implantable intravascular stent comprising: (a) a stent sidewall structure comprising a plurality of struts each having an abluminal surface and an adluminal surface; (b) a first coating disposed on the abluminal surface of at least one strut comprising: (i) a first coating composition comprising an anti-restenosis agent disposed upon at least a portion of the abluminal surface of the strut, wherein the first coating composition when disposed on the portion of the surface of the abluminal surface of the strut has an outer surface; and (ii) a second coating composition comprising a metallic material disposed on at least a portion of the first coating composition, wherein the second coating composition is substantially free of any polymer; and wherein after the second coating composition is applied to the portion of the first coating composition the second coating composition comprises an outer surface and a plurality of pores, in which the pores extend from the outer surface of the first coating composition to the outer surface of the second coating composition; and (c) a second coating disposed on at least a portion of the adluminal surface of the at least one strut comprising the first coating composition.
 24. An implantable intravascular stent comprising: (a) a stent sidewall structure comprising (1) a plurality of struts each having an abluminal surface and an adluminal surface, and (2) openings in the stent sidewall structure; (b) a first coating disposed on the abluminal surface of at least one strut comprising: (i) a first coating composition comprising an anti-restenosis agent disposed upon at least a portion of the abluminal surface of the strut, wherein the first coating composition when disposed on the portion of the surface of the abluminal surface of the strut has an outer surface; and (ii) a second coating composition comprising a metallic material disposed on at least a portion of the first coating composition, wherein the second coating composition is substantially free of any polymer; and wherein after the second coating composition is applied to the portion of the first coating composition the second coating composition comprises an outer surface and a plurality of pores, in which the pores extend from the outer surface of the first coating composition to the outer surface of the second coating composition; and (c) a second coating disposed on at least a portion of the adluminal surface of the at least one strut comprising the first coating composition, wherein the adluminal surface of the at least one strut is free of the second coating composition; and wherein the first and second coatings conform to the stent sidewall structure to preserve the openings therein.
 25. An implantable intravascular stent comprising: (a) a stent sidewall structure having a surface; and (b) a coating comprising: (i) a first coating composition comprising a therapeutic agent disposed upon at least a portion of the surface of the stent sidewall structure wherein the first coating composition has a first thickness; and (ii) a second coating composition comprising a metallic material disposed upon at least a portion of the surface of the stent sidewall structure, wherein the second coating composition has a second thickness and is substantially free of any polymer; and wherein the second thickness of the second coating composition is the same as or greater than the first thickness of the first coating composition.
 26. The stent of claim 25, wherein the second thickness of the second coating composition is greater than the first thickness of the first coating composition.
 27. The stent of claim 25, wherein the first thickness of the first coating composition is equal to the second thickness of the second coating composition.
 28. The stent of claim 25, wherein the first coating further comprises a polymer.
 29. The stent of claim 25, wherein the second coating composition is disposed adjacent to the first coating composition on the surface of the stent sidewall structure.
 30. The stent of claim 25, wherein the stent sidewall structure comprises a plurality of struts and openings and the surface of the stent sidewall structure is the abluminal surface of the stent. 